National Institute for Public Health Nanotechnology and the Environment What about safety How do we determine risk? Wim H. de Jong, DVM, PhD
Expected increase in use of nanomaterials • Possible applications - Material science • Strenght of materials (especailly CNT) - Consumer products • Cosmetics (sunscreens) • Fabrics • ........... - Food/feed and food technology • Packaging • Vitamins, supplements • ……….. - Medical applications • Pharmaceutical (drug delivery, enhanced activity) • Medical technology National Institute for Public Health and the Environment
Nano- technologies Tissue Engineered Products Gene Therapy Drug/device combinations Materials science Smart materials Minimally invasive surgery Computer-assisted surgery systems Active medical devices Artificial organs Biological Telemedicine sciences Medical Imaging Diagnostics (lab on a chip) Information technology Cognitive sciences Converging technologies National Institute for Public Health and the Environment
Why do we use nanomaterials? Decrease in size results in increase in surface area All: 1 x 1 cm size number Total Surface area 6 cm 2 1 cm 1 60 cm 2 1 mm 1000 1 x 10 12 6.000cm 2 1 µm 60.000.000 cm 2 1 x 10 21 1 nm (600km 2 ) Increase in surface area >> increase in surface activity, but also increase in possible contact with cells and tissues National Institute for Public Health and the Environment
Increase in consumer products with nanoclaim Number of total products listed, by date of inventory update, with regression analysis. August 2009 Nanotechnology Consumer Products Inventory, Woodrow Wilson International Center for Scholars, Washington, USA National Institute for Public Health and the Environment
Most commonly used nanomaterials in consumer products Nanotechnology Consumer Products Inventory, August 2009, Woodrow Wilson International Center for Scholars, Washington, USA National Institute for Public Health and the Environment
Why are we concerned? Nature water DNA virus erythrocyte apple molecule 10 -1 10 1 10 2 10 3 10 4 10 5 10 6 10 7 10 8 1 Nanometres Nanotechnology nanopore, dendrimer, cantilevers, lab-on-a-chip nanoshell, fullerene, microneedles nanotube, nanowire, nanocrystalls Nanomaterials (nanoparticles) can have sizes similar to structures at subcellular level and (theoretically) can reach and interact with such structures. National Institute for Public Health and the Environment
Safety evaluation • Safety evaluation - Identification of substance - Hazard characterization • Hazard identification • Dose response effect (no effect level) - Exposure assessment/ treatment dose • What is risk? - Risk, combination of likelyhood of occurrence of harm to health and the severity of that harm - Margin of safety (no effect level / effective treatment dose) - (No exposure >>>>> No risk) • Residual risk - Risk benefit analysis • Risk is a possibility, not an absolute value ! National Institute for Public Health and the Environment
How do you determine risk? • Hazard, a potential source for harm to health • In vitro studies - Indicate possibility for cell damage - Mainly used for to screening and mechanistic studies - Relevance for risk assessment is limited • In vivo studies - Overall “black box” - Indications for possible organ specific toxic effects and no effect levels - Extrapolation problems (inter- and intraspecies variation) • Uncertainty factors - More relevant for risk assessment than in vitro National Institute for Public Health and the Environment
Why is safety evaluation and risk assessment of nanomaterials so difficult? • Diversity of nanomaterials (inorganic, organic, coated,…) • Solubility, agglomeration/aggregation (stability, size distribution) • Matrix (interactions, effects on size, digestion) • Quality of available nanomaterials (polydispersity, purity, concentration) • Test protocols (dispersion, reproducibility, comparability) • Choice & preparation of test medium (concentration, solvents) Key issue in testing and quality control Detection and characterization of the nanomaterials National Institute for Public Health and the Environment
For safety evaluation identification is essential What do we want / need to know for nanoformulations / carriers? • Chemical composition • Size • Size distribution • Agglomeration / aggregation • Crystallinity • Coatings • Surface charge • Specific physicochemical characteristics - why is this specific nanomaterial used? • mainly important for consumer products • ………. • How is the nanoparticle defined? National Institute for Public Health and the Environment
How is a nanoparticle/nanomatrial defined? What do we mean by size? TEM, transmission electron microscopy; AFM, atomic force microscopy; DLS, dynamic light scattering; FCS, fluorescence correlation spectroscopy; NTA, nanoparticle tracking analysis; FIFFF, flow field flow fractionation National Institute Courtesy of Karin Tiede, FERA, York, UK for Public Health and the Environment
Existing problems in safety evaluation of nanomaterials/nanoparticles • Identification of nanomaterial is essential - Various crystal forms of same material may exist • Titanium dioxide; rutile, anatase, brookite crystals - Presence of coating on nanomaterials • Each different coating can be considered a new formulation / material Rutile TiO 2 Anatase TiO 2 National Institute for Public Health and the Environment
Particle size and agglomeration Example of nominal and actual size of silica nanoparticles 10 (11) 30 (34) 400 (248) 80 (34) Transmission electron microscopy images of silica nanoparticles deposited from deionized water. National Institute Park et al., Toxicol Appl Pharmacol, 2009 for Public Health and the Environment
Safety evaluation • Problems with testing - Problems with identification/characterization - Problems with dispersion for testing in vitro and/or in vivo - Protein adherence, effect of protein corona - We now it exists, but we do not know its biological effects National Institute for Public Health and the Environment
Nanoparticles do not exist as single particle entity, they adsorbe things, e.g. proteins What do we know - Protein corona is important for biological interactions and cellular recognition - Corona is not static, proteins get on and off What do we not know - Dependence on nanomaterial? - Dependence on size? - Dependence on …? Implications for interpretation of testing EU FP6 project NanoInteract, courtesy of Prof Kenneth Dawson, UCD, Dublin, Ireland National Institute for Public Health and the Environment
What is the dose metric for particle toxicity? Surface area was demonstrated to be a better descriptor for local effects in the lung after inhalation exposure. What about other routes of exposure (oral, dermal, intravenous)? National Institute Oberdörster et al., Environ Health Perspect 113, 823, 2005 for Public Health and the Environment
Is dose metric of mass applicable? • Dose metrics per kg body weight - Mass (milligram, gram) - Number of particles, as effects may be determined by the particle characteristics - surface area, as demonstrated for inhalation toxicity of TiO 2 - ..........something else? National Institute for Public Health and the Environment
Pharmacological availability Effect of nanoparticle size on tissue distribution 10 nm 4.0% 10 nm 60% 50 nm 50 nm 3.5% 100 nm 100 nm 50% 250 nm 250 nm Amount of ditsibuted gold Amount of ditsibuted gold 3.0% (% of injected dose) (% of injected dose) 40% 2.5% 30% 2.0% 1.5% 20% 1.0% 10% 0.5% 0% 0.0% Blood Liver Spleen Lungs Kidneys Repr. Thymus Heart Brain Spleen Lungs Kidneys Repr. Thymus Heart Brain Organs Organs Gold distribution at 24 h after iv injection in rats as percentage of injected dose (100 µg per animal) Particle size 10 nm 50 nm 100 nm 250 nm Number concentration 5.7x10 12 4.5x10 10 5.6x10 9 3.6x10 8 Surface area 1.6x10 15 3.2x10 14 1.7x10 14 6.9x10 13 Mass injected 85 µg 106 µg 98 µg 120 µg National Institute De Jong et al., Biomaterials, 2008 for Public Health and the Environment
Pharmacological availability Effcets of size on toxicokinetics Although only a few % of the administered dose a considerable amount may be present in organs in terms of particle numbers. What about local accumulation and chronic effects? National Institute De Jong et al., Biomaterials, 2008 for Public Health and the Environment
Pharmacological availability Effects of PEG coating of gold nanorods on toxicokinetics Blood clearance of PEGylated and non PEGylated Au nanorods 2500 Control PEG-AuNR 2000 Au blood level (ng/g) CTAB-AuNR 1500 0.5 1000 -1 ) 0.4 Extinction coefficient (mm 500 Non- PEGylated AuNR PEGylated AuNR 0.3 0 0.2 -96 0,25 0,5 1 2 4 8 24 48 96 144 192 Time after injection (hour) 0.1 0.0 400 500 600 700 800 900 wavelength (nm) National Institute Lankveld et al., Submitted, 2010 for Public Health and the Environment
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